Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8+ T lymphocytes

• Published in: Neuron (Cambridge, Mass.) Vol. 111; no. 5; pp. 696 - 710.e9
• Main Authors: Shi, Zhongshan, Yu, Pei, Lin, Wei-Jye, Chen, Sitai, Hu, Xia, Chen, Siqi, Cheng, Jinping, Liu, Qiang, Yang, Yuhua, Li, Shaojian, Zhang, Zhan, Xie, Jiatian, Jiang, Jingru, He, Baixuan, Li, Yi, Li, Honghong, Xu, Yongteng, Zeng, Junbo, Huang, Jialin, Mei, Jinghong, Cai, Jinhua, Chen, Jiongxue, Wu, Long-Jun, Ko, Ho, Tang, Yamei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2023
• Subjects: Animals; Brain - metabolism; Brain Injuries - pathology; CD8+ T cell; CD8-Positive T-Lymphocytes - metabolism; chemoattraction; Chemokine CCL2 - metabolism; ischemic stroke; Mice; Mice, Inbred C57BL; microglia; Microglia - physiology; radiation-induced brain injury; radiation-induced brain injury; CD8+ T cell; microglia; ischemic stroke; chemoattraction; CD8(+) T cell
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.12.009

The crosstalk between the nervous and immune systems has gained increasing attention for its emerging role in neurological diseases. Radiation-induced brain injury (RIBI) remains the most common medical complication of cranial radiotherapy, and its pathological mechanisms have yet to be elucidated. Here, using single-cell RNA and T cell receptor sequencing, we found infiltration and clonal expansion of CD8+ T lymphocytes in the lesioned brain tissues of RIBI patients. Furthermore, by strategies of genetic or pharmacologic interruption, we identified a chemotactic action of microglia-derived CCL2/CCL8 chemokines in mediating the infiltration of CCR2+/CCR5+ CD8+ T cells and tissue damage in RIBI mice. Such a chemotactic axis also participated in the progression of cerebral infarction in the mouse model of ischemic injury. Our findings therefore highlight the critical role of microglia in mediating the dysregulation of adaptive immune responses and reveal a potential therapeutic strategy for non-infectious brain diseases. [Display omitted] •Combined scRNA and TCR sequencing of human brain tissues with injury•Infiltrated CD8+ T cells participate in radiation-induced and ischemic brain injuries•Disease-associated microglial cluster featured with CCL2 and CCL8 expression•Microglia-derived CCL2/CCL8 mediate brain infiltration of CD8+ T cells Using single-cell transcriptomic and immune repertoire sequencing, Shi et al. identify a chemotactic action mediated by microglia-derived CCL2/CCL8 chemokines in recruiting CD8+ T cells. These cause brain injuries in radiation-induced brain injury and ischemic stroke models, providing mechanistic insight and a potential therapeutic strategy for non-infectious brain diseases.